Human CD1 molecules are a subfamily of MHC class I molecules capable of presenting foreign antigens to T-cells. One feature of CD1 is its unique tissue distribution, with prominent expression in skin. However, the role of CD1 in mediating immunologic responses has not been elucidated. Since CD1 molecules are nonpolymorphic, CD1-restricted T-cells from individuals with different genetic backgrounds are likely to recognize identical or similar antigens/epitopes. The identification of these antigens should provide new insight into the CD1 presentation pathway and its role in immunologic responses. To investigate the CD1 presentation pathway, we have chosen to study the skin lesions of leprosy as a model. We have found that the expression of CD1+ cells in these skin lesions correlates with the level of cell- mediated immunity against the causative agent of leprosy, M. leprae. Furthermore, we have successfully derived antigen-reactive CD1-restricted T-cells from such lesions. To elucidate the role of CD1 molecules in skin, we first propose to derive antigen-specific CD-1 restricted alpha- beta+, CD4-, CD8- (double negative) T-cells from leprosy skin lesions and measure their effector function in terms of cytokine pattern and cytotoxicity. The chemical nature of the CD1-restricted antigens will be investigated, both nonpeptide and peptide ligands, consistent with our preliminary results that both types of molecules can be presented by CD1. The mechanism by which both types of antigens are processed and presented via the CD1 pathway will be investigated. Finally, the T-cell receptor (TCR) repertoire of antigen-specific cells will be studied to learn the mechanism of TCR-antigen-MHC interaction and to examine the frequency and distribution of CD1-restricted T-cells in skin. We believe that these studies will provide insight into the immunoregulatory role of CD1- restricted T-cell responses.